The serine/theronine kinase Akt, perhaps the most frequently activated oncoprotein in human cancers, and whose activation often exerts chemoresistance, is an attractive target for cancer therapy. Our long-term goals are to understand why Akt is frequently activated in human cancers, and to elucidate the mechanisms by which Akt activation contributes to the genesis of cancer, a critical step toward enhancing such therapy. We are using genetic approaches to evaluate the feasibility and the physiological consequences of Akt ablation for cancer therapy. Over the years, we have been delineating the functions of Akt both at the cellular and organismal levels. By employing mouse knockouts of the Akt genes, we uncovered several mechanisms by which Akt activity contributes to cell survival, cell proliferation, and susceptibility to oncogenic transformation. We employed several mouse models to show that Akt1 ablation inhibits the development of neoplasia in these models. The current major objectives of this grant application, at the cellular level, include understanding the role of Akt in cell proliferation and tumorigenesis and its dependence on mTORC1. At the organismal level, we will employ conditional deletions of the Akt genes in the mouse to determine the therapeutic effect on cancer developed in these mice. We will verify and further understand the consequences of Akt1 deletion versus Akt2 deletion on cancer development, progression and metastasis. Finally, we will assess whether the conditional deletion of hexokinase 2, a downstream effector of Akt, could affect tumor development, and whether it could be targeted for cancer therapy.